Materials for Pharmaceutical Manufacturing

Materials for Pharmaceutical Manufacturing GRACE WHITEPAPER FP Excipients 2-Step Mixing Process Improves API Stability, Flow, and Uniformity Technical Development: Dr. Raghunadha Gupta - Formulation Scientist, Grace Indian Knowledge Center, Hyderabad India Dr. Chitra Sundararajan - Lab Manager, Grace Indian Knowledge Center, Hyderabad India Fred Monsuur - Business Segment Leader, Pharmaceutical Excipients, Grace Lokeren Belgium synthesis intermediates purification technologies formulation and delivery M433

Introduction Two-Step Mixing Process Tablet preparation through Direct Compression is preferred over wet and dry granulation due to its reduced complexity, fewer steps, lower cost, and faster development time. The steps involved in direct compression are blending the API with excipients (e.g.: filler, disintegrant, binder) and compaction of the total mixture into tablets. Direct compression is particularly beneficial for APIs that are sensitive to moisture and heat by avoiding granule preparation process. The three most important factors for successful tabletting by direct compression are flow, compactability of the compression mix and drug content uniformity in the final mix and tablets. Flowability of the powder is the most important factor and unfavorable flow affects the tablet weight uniformity and processability. Flowability of the final mixture is a big concern in the case of high dose drugs and the content uniformity is in the case of low dose drugs. The drug properties also influence the flow and compactability of the final mixture for tablet preparation. Glidants are added to the formulation to improve flow properties of the mixture for tabletting. The effect of glidants on the flow of granules depends on the shape and size of the glidant particle and the granule. Flow of the final mixture depends on a combination of particle size, molecular interactions, tribo-eletrostatic charges, presence of polar groups and capillary forces. The procedure used for the addition of glidant can also influence the flow of the mixture. Porous silica gel, such as silica, is advantageous for flow improvement compared to other Using AL-1FP/63FP to Protect Moisture Sensitive APIs... In Formulation: Moisture sensitive APIs are prone to caking, flow issues, and inconsistent dissolution ADSORPTION CAPACITY, WEIGHT % 1 12 1 8 6 2 244FP 72FP AL-1FP/63FP Fumed MAXIMUM POROSITY NO POROSITY 1 2 3 5 6 7 8 9 1 RELATIVE HUMIDITY% Figure 1. The higher surface area and internal porosity gives FP silicas greater moisture adsorption than other silicon dioxide excipients. Having a range of adsorption capacities makes FP silicas the ideal choice for both the API mixing and the excipient mixing stages of a two-step mixing process. glidants because of its porous nature and reduced dust due to its high density. Apart from improving flow properties, porous silica gel can also promote uniformity and improve stability of the API by adsorbing moisture present in the final formulation. Specifically, AL-1FP/63FP excipients are recommended for stability improvement of moisture sensitive APIs. It has been shown [Abe et al, Chem. Pharm. Bull. 57(7) 647 652 (29] that addition of a glidant separately to both the API and the excipients mixture can have a beneficial effect on the flow property. When the glidant was added separately to the API and excipient mixtures (two-step glidant mixing), flow improvement was more pronounced than if the glidant was added as a single step to the entire API and excipient formulation mixture (one-step glidant mixing). In this work, we will demonstrate the use of FP silicas for flow improvement through a two-step glidant mixing process. Also, we demonstrate that the two-step mixing strategy can be used to impart additional benefits to the formulation such as moisture control, stability, and uniformity through the use of appropriate types of porous silicas. POROSITY (PS/PV) For Shelf Life: Moisture sensitive APIs can degrade quickly, reducing their shelf life if not protected from moisture Before considering special packaging to protect moisture sensitive formulations, first consider selecting the right excipients and formulation techniques to help stabilize moisture sensitive APIs. Porous silica gel, such as FP silicas, can help improve the stability of moisture sensitive APIs by adsorbing moisture in the final formulation. 2

2-Step Mixing Process Part A: Improving Flow Property and Uniformity by Adding Glidant ( 244FP silica) in Two-Step Mixing Process compared to One-Step Mixing. Here, we tested the flow improvement by using one-step versus two-step incorporation of silica as a glidant, with two high-dose API formulations (Paracetamol 5% and Ascorbic Acid %). The assumption here is that in one-step mixing, the amount of FP silica as a glidant is diluted by the total excipient mixture and is insufficiently available to form a layer and protect the API particle. In a two-step process, the amount of FP silica is sufficiently available to form a layer around the API particle, thus improving flow, uniformity, and stability. In addition, Two-step mixing ensures uniform distribution of the API throughout the formulation due to the micronized excipient/ excipient and excipient/api particle compatibility, which prevents segregation. Procedure for preparation of samples for two step glidant mixing: Initially, we determined the percentage of silica required for separately improving the flow of fine powder drugs such as ascorbic acid (passed through Mesh), Paracetamol (passed through 6 Mesh) and the excipient portion present in the respective formulations. Fine APIs and the excipients were separately mixed with silica at different amounts. The optimum percentage of silica was identified with respect to the individual API and with respect to the excipient mixture (see Chart 1 on the following page). In a one-step glidant mixing process, there is an insufficient amount of glidant to surround the API and protect it from moisture due to the fact that the glidant is distributed throughout the formulation mixture Figure 2: One-Step Glidant Mixing Process API Filler Binder Disint. Lubricant API / Excipient / Glidant Mixing Figure 3: Two-Step Glidant Mixing Process Using In a two-step glidant mixing process, there is a sufficient amount of glidant to surround the API API Filler Binder Disint. Lubricant Step 1 API Mixing Excipient Mixing Step 2 Final Direct Compression Mixing

1-Step vs 2-Step Mixing - Flow Properties Chart 1. 2-Step Mixing and effect of silica % on flow property in the API Mix (Step 1) and the Excipient Mix (Step 2) Ascorbic Acid Formulation: 35 33 31 29 27 25 42 Step 1 - API Mix with Ascorbic Acid 1 2 3 Amount of Glidant (%) Step 2 - Excipient Mix.5 1 1.5 2 Amount of Glidant (%) Paracetamol Formulation: Optimum amounts of silica were determined for the API Mix (Step 1) and the Excipient Mix (Step 2). They were then blended and the resulting mixtures were evaluated for flow parameters. A typical direct compression formulation was prepared with % Ascorbic acid, 2.5% PVP K 3, 3.3% croscarmellose sodium,.75% stearic acid, and.35-1.4% glidant. The remaining amount was MCC PH 12 to bring the mixture to 1g. As seen in Chart 2 below, there is a significant improvement in flow property when glidant is added to the ascorbic acid formulation. Furthermore, adding glidant in two separate steps to the API and excipient mixtures provides better flow behavior than a single-step process. silica was also compared with fumed silica at the optimized amounts. Flow improvement with silica was similar or slightly better than fumed silica. 32 3 No Glidant Chart 2. Ascorbic Acid Flow.35% 2-Step vs 1-Step.35% Fumed.7% 1.4% 2-Step 1-Step 6 55 5 45 35 3 Step 1 - API Mix with Paracetamol 1 2 3 Amount of Glidant (%) To confirm the above observations, a similar procedure was used on a Paracetamol formulation with 5% API, 5% PVP K 3, 2.5% croscarmellose sodium,.5% Mg stearate,.35-1.4% glidant. The remaining amount was MCC PH 12 to bring the mixture to 1g. 46 44 42 Chart 3. Paracetamol Flow 2-Step vs 1-Step 2-Step 1-Step 39 37 35 33 Step 2 - Excipient Mix.5 1 1.5 Amount of Glidant (%) No Glidant.375%.375% Fumed.75% 1.5% From the results above, we conclude that silica can be used as a glidant in a two-step mixing process to obtain maximum glidant benefits. In comparison to fumed silica, shows similar or slightly better flow improvement. We also observe that flow improvement depends on the percentage of the API as well as the particle size of the API. 4

2-Step Mixing Process - Protecting Moisture Sensitive APIs Part B: Adding Different Grades in a Two-Step Mixing Process to Protect Moisture Sensitive APIs, Improve Uniformity and Stability While Maintaining Good Flow Behavior In addition to flow improvement, porous silica gel, can also help improve the stability of moisture sensitive APIs by absorbing moisture present in the final formulation. Porous silica gel, such as silica, is typically used as a glidant in formulations in small amounts (up to 2%). However, for adequate moisture protection, such low quantities are not sufficient. Another grade of porous silica, AL-1 FP/63FP (AL-1FP for EU, 63FP for US) silica, is particularly effective for providing moisture protection and can be incorporated in larger amounts depending on the critical relative humidity as well as the nature and amount of API in the formulation. Here, we demonstrate that incorporating the two different grades of porous silicas ( AL-1/63FP silica and 244 FP silica) through two-step mixing can provide the combined benefits of moisture protection and flow improvement to the formulation. We also demonstrate that greater quantities of porous silica (5-2%) required to provide moisture protection can be used, while maintaining compressibility of the formulation mixture. silica is used here in the excipient part of the formulation, to lend its glidant property to the mixture. AL-1/63FP silica, which is specifically for moisture control of sensitive molecules, is mixed with the API to absorb moisture and provide stability to the formulation mix. Figure 4: Two-Step Mixing Process of Moisture Adsorbing and Glidant Protects API from Moisture API AL1-FP/63FP Improves Flow Properties Filler Binder Disint. Lubricant Step 1 API Mixing Excipient Mixing Step 2 Final Direct Compression Mixing Ascorbic acid was used as a model drug in a direct compression formulation to demonstrate the effects of different amounts of silica on flow and tablet parameters. We evaluated the effect of different amounts of AL-1/63FP silica on the flow behavior and the compressibility of the final formulation, with both 1% and % drug loading. silica is used at 1% in all the formulations to provide optimum glidant benefits. The amount of AL-1/63FP silica was varied from 5% up to 2% of the formulation. Table 1. Formulations containing different amounts of AL-1FP/63FP silica Formulation (%) A B C D E AL-1/63FP 5 1 15 2 Ascorbic Acid 1 1 1 1 1 MCC PH 12 82.3 52.3 77.3 47.3 72.3 42.3 67.3 37.3 62.3 32.3 PVPK 3 2.5 2.5 2.5 2.5 2.5 Cross Povidone 3.35 3.35 3.35 3.35 3.35 1 1 1 1 1 Stearic Acid.85.85.85.85.85 Total 1 1 1 1 1 5

2-Step Mixing - Tabletting Results Results and Discussion: We first tested the flow parameters of the final formulation with and without AL-1/63FP silica at different percentages. The mixtures were then compressed into tablets by direct compression. The resulting tablets were evaluated for various parameters such as hardness, friability, weight uniformity, etc. Chart 4. Effect of different amounts of AL-1/63FP silica on flow property Angle of Repose 46 44 % API 42 1% API 5 1 15 2 25 % of AL-1/63FP Table 2. Tablet parameters with different amounts of AL-1/63FP silica Formulation (%) A B C D E AL-1/63FP 5 1 15 2 Ascorbic Acid (%) 1 1 1 1 1 Weight (mg) 5 5 5 5 5 5 5 5 5 5 Weight Uniformity, RSD %.48.79.33.96.82.6.5 1.64.8 1.5 Hardness (Kg/Cm 2 ) 12.5 1 12 7.5 11 5.5 9 3.5 7 2 Disintegration Time (min) 24 8.1 19.5 5.3 14.5 1.54 5..47 4.3.25 Friability (%).33 1 > Compression Force (KN) 27-28 -42 27-28 -42 27-28 -42 27-28 -42 27-28 -42 For formulations with lower loading of API, AL-1/63FP silica can be added for moisture protection up to 2% of the total formulation, while still maintaining good flow of the resulting mix and good tablet properties. We successfully demonstrate that tablets can be prepared by direct compression method using AL-1/63FP silica from 5% to 2% at different API loading 1% and %. We found that the tablet properties are very good with 1% API loading at all percentages of AL-1/63FP silica from 5% to 2%. For % API loading, the tablet properties are good with up to 15% AL-1/63FP silica. Chart 5. Effect of different amounts of AL-1/63FP silica on tablet hardness Chart 6. Weight uniformity of tablets containing different amounts of AL-1/63FP silica Hardness (kg/cm 2 ) 14 12 1 8 6 4 2 5 1 15 2 % of AL-1/63FP 1% API % API Tablet Weight Uniformity, % RSD 1.8 1.6 1. 1.2 1..8.6..2. 5 1 15 2 % of AL-1/63FP 1% API % API 6 *Tablet weight variation is measured as a function of RSD% of the tablet weights. Lower weight variation and better uniformity results in lower RSD%.

Conclusion Conclusions: FP silicas can provide the dual benefits of flow improvement and moisture protection when incorporated into formulations in a two-step mixing process. The tablet parameters such as hardness, friability, and weight uniformity were found to depend on both percentage of API and percentage of AL-1/63FP silica in the tablets. By optimizing these ratios for different drugs, sufficient amounts of porous silicas can be incorporated for direct compression to provide optimal moisture protection to the formulation. We are currently investigating the effects of large amounts of silica on other parameters like disintegration times and dissolution rates. Abbreviations: A.R. - Angle of Repose CI - Carr s Index or Compressibility Index HR - Hausner s Ratio SD - Standard Deviation RSD - Relative Standard Deviation Materials for Pharmaceutical Manufacturing Grace is the world s largest manufacturer of specialty silica gel and a leading supplier of chromatography media. We offer an extensive portfolio of products and services to support pharmaceutical manufacturing. synthesis intermediates Chiral Building Blocks Custom Synthesis Grace s Synthetech products and contract manufacturing services support pharmaceutical companies synthesis needs to bring new drugs to market faster. Our in-depth understanding of chemical synthesis, expertise in complex transformations, and understanding of pharmaceutical processes form strong collaborative relationships with our customers. With grams to tons capacity, we are equipped to be your preferred one-stop source from preclinical to commercial volumes. purification technologies Bulk Chromatographic Media DAC Systems and Column Packing Expertise Grace has nearly 1 years experience in silica engineering technology. This experience helps deliver better chromatographic performance, improved capacity, and higher purity silica for purification needs from clinical trials through large-scale manufacturing. As one of the first media platforms for reversed-phase protein and peptide separations, Grace s Vydac media remains a trusted name in biopurification. We complement our media offering with innovative column and packing solutions. formulation and delivery Multi-functional Excipients -Based Drug Delivery The advanced adsorptive properties of FP silica excipients help pharmaceutical companies improve formulations and streamline manufacturing processes. Our excipients meet the high quality and regulatory standards the pharmaceutical industry demands. If your need goes beyond excipients and you require a customized silicabased drug delivery solution, Grace has formed a collaborative relationship with Formac Pharmaceuticals to develop a high-throughput screening platform to identify optimal silica-drug combinations for drug delivery of poorly water-soluble drugs. 7

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